Discovery of a Proneurogenic, Neuroprotective Chemical

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Cell (Impact Factor: 33.12). 07/2010; 142(1):39-51. DOI: 10.1016/j.cell.2010.06.018
Source: PubMed

ABSTRACT An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:

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Available from: Noelle S Williams, Jul 31, 2015
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    • "Once activated, microglia proliferate rapidly and secrete pro-inflammatory cytokines, chemokines, and neurotoxic molecules that contribute to a toxic microenvironment leading to neuronal death (Beggs and Salter, 2007; Block et al., 2007; Benarroch, 2013). P7C3 has been shown to foster stabilization of mitochondrial membrane potential in the face of otherwise overwhelming toxic insult (Pieper et al., 2010),and P7C3 may be acting directly on neurons in our model. In our model, neuronal Fig. 6. "
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    ABSTRACT: Nerve injuries cause pain, paralysis and numbness that can lead to major disability, and newborns often sustain nerve injuries during delivery that result in lifelong impairment. Without a pharmacologic agent to enhance functional recovery from these injuries, clinicians rely solely on surgery and rehabilitation to treat patients. Unfortunately, patient outcomes remain poor despite application of the most advanced microsurgical and rehabilitative techniques. We hypothesized that the detrimental effects of traumatic neonatal nerve injury could be mitigated with pharmacologic neuroprotection, and tested whether the novel neuroprotective agent P7C3 would block peripheral neuron cell death and enhance functional recovery in a neonatal nerve injury model. Administration of P7C3 after sciatic nerve crush injury doubled motor and sensory neuron survival, and also promoted axon regeneration in a dose-dependent manner. Treatment with P7C3 also enhanced behavioral and muscle functional recovery, and reversed pathological mobilization of spinal microglia after injury. Our findings suggest that the P7C3 family of neuroprotective compounds may provide a basis for the development of a new neuroprotective drug to enhance recovery following peripheral nerve injury.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.005 · 3.33 Impact Factor
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    • "Neurogenesis in mouse hippocampus was measured as previously described (Pieper et al., 2010). The animal experiments were approved by the University of Texas Southwestern Medical Center Institutional Animal Care and Use Committee. "
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    ABSTRACT: Highlights •The P7C3 class of chemicals protects cells from doxorubicin-mediated toxicity •NAMPT is identified as the intracellular target of P7C3 •P7C3 chemicals restore NAD levels in doxorubicin-treated cells •P7C3 chemicals enhance the enzymatic activity of NAMPT in vitro Summary The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
    Cell 09/2014; 158(6):1324–1334. DOI:10.1016/j.cell.2014.07.040 · 33.12 Impact Factor
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    • "Compound formulation was conducted using previously described methods (Pieper et al., 2010, Naidoo et al., 2014). "
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    ABSTRACT: The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage. Initiation of daily treatment with our recently reported lead agent, P7C3-S243, 1 day after blast-mediated TBI blocks axonal degeneration and preserves normal synaptic activity, learning and memory, and motor coordination in mice. We additionally report persistent neurologic deficits and acquisition of an anxiety-like phenotype in untreated animals 8 months after blast exposure. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both, such as occurs in TBI.
    Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.030 · 7.21 Impact Factor
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